Treatment of adenoviral infection or diseases associated with adenoviral infection

Abstract

To provide treatment of adenoviral infection or diseases associated with adenoviral infection.SOLUTION: Disclosed is a pharmaceutical composition for the treatment of adenoviral infection or a disease associated with adenoviral infection comprising Brincidofovir, pharmaceutically acceptable salt or solvate thereof, where the treatment comprises (i) intravenous administration of Brincidofovir, pharmaceutically acceptable salt or solvate thereof at a dosage of 0.38 to 0.42 mg / kg twice a week to a human subject, or (ii) intravenous administration of Brincidofovir, pharmaceutically acceptable salt or solvate thereof at a dosage of 18 to 22 mg / once twice a week to a human subject.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The technical field of the invention relates to the treatment of adenoviral infections or diseases associated with adenoviral infections. [Background technology]

[0002] Brincidofovir (BCV) was approved by the U.S. Food and Drug Administration (FDA) in 2021 as a treatment for smallpox. Non-Patent Document 1 describes the benefit-risk assessment of BCV in smallpox treatment. In addition, Non-Patent Document 2 describes that monkeypox has begun to spread since May 2022, and that the use of BCV is recommended for the management of confirmed cases. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] "Benefit-risk assessment for brincidofovir for the treatment of smallpox: US Food and Drug Administration's Evaluation" Chan-Tack et al., Antiviral Res. 2021 Nov;195:105182. [Non-Patent Document 2] "Monkeypox: A Mini-Review on the Globally Emerging Orthopoxvirus" Evans et al., Int J Environ Res Public Health. 2022 Nov 25;19(23):15684. Summary of the Invention [Problem to be solved by the invention]

[0004] Many points remain unclear regarding the therapeutic effect and treatment method of adenovirus infection or diseases associated with adenovirus infection using BCV.

[0005] On the other hand, the inventors of the present application have demonstrated that intravenous administration of BCV using a specific method and dosage exhibits particularly excellent therapeutic effects against adenovirus infection or diseases associated with adenovirus infection, as described in the Examples below. [Means for solving the problem]

[0006] According to one aspect of the present invention, there is provided a pharmaceutical composition for treating adenovirus infection or a disease associated with adenovirus infection, comprising brincidofovir, a pharma- ceutical acceptable salt or a solvate thereof, and the treatment comprises (i) administering brincidofovir, a pharma- ceutical acceptable salt or a solvate thereof intravenously to a human subject at 0.38-0.42 mg / kg twice weekly, or (ii) administering brincidofovir, a pharma- ceutical acceptable salt or a solvate thereof intravenously to a human subject at 18-22 mg / administration twice weekly. Use of this pharmaceutical composition provides a particularly excellent therapeutic effect against adenovirus infection or a disease associated with adenovirus infection. [Brief description of the drawings]

[0007] [Figure 1] The study results for Cohort 1 are shown. [Diagram 2] The study results for cohort 2 are shown. [Diagram 3] The study results for cohort 3 are shown. [Figure 4] The results of examining the amount of AdV in stool are shown. [Diagram 5] The results of examining lymphocyte counts in patients in cohort 3 are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Hereinafter, the embodiments of the present invention will be described in detail. Note that, in order to avoid repetition and complexity, the description of similar contents will be omitted as appropriate.

[0009] (1) Method According to one embodiment of the present invention, there is provided a method for treating an adenovirus (AdV) infection or a disease associated with AdV infection, comprising administering brincidofovir (BCV), a pharma- ceutically acceptable salt or a solvate thereof to a subject. In this method, the administering step may comprise (i) administering 0.38 to 0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously twice a week to the subject, or (ii) administering 18 to 22 mg of BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously twice a week to the subject. By utilizing this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the amount of AdV reaches below the detection limit, shorten the treatment period, or provide a treatment with excellent safety.

[0010] (2) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt or a solvate thereof to a subject, the administration step comprising (i) administering 0.38-0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly to a subject below a certain weight, or (ii) administering 18-22 mg / intravenously twice weekly to a subject above a certain weight, the certain weights in (i) and (ii) being the same, 48-52 kg. By utilizing this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the amount of AdV reaches below the detection limit, shorten the treatment period, or provide a treatment with excellent safety.

[0011] (3) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt or a solvate thereof to a subject, the administration step comprising: (i) administering 0.38 to 0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to a subject twice a week (however, in an environment in which cyclosporine is used in combination, the dose of BCV, a pharma- ceutically acceptable salt or a solvate thereof is reduced to 55 to 65%); or (ii) administering 18 to 22 mg of BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to a subject twice a week (however, in an environment in which cyclosporine is used in combination, the dose of BCV, a pharma- ceutically acceptable salt or a solvate thereof is reduced to 55 to 65%). This method can be used to reduce the occurrence of treatment failure in patients, shorten the time until the AdV amount reaches undetectable levels, shorten the treatment period, or provide a safer treatment.

[0012] (4) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof to a subject, in which, when the administering step is not performed in an environment in which cyclosporine and BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof are co-administered, the method can be performed by (i) administering BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof intravenously to a subject at 0.38 to 0.42 mg / kg twice weekly, or (ii) administering BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof intravenously to a subject at 0.5 to 10 mg / kg twice weekly. and administering 18 to 22 mg of a solvate thereof twice weekly, wherein the administering step is carried out in an environment of coadministration of cyclosporine and BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof, the administering step comprises (i) administering 0.21 to 0.27 mg / kg of BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject, or (ii) administering 9.9 to 14.3 mg of BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof twice weekly to a subject. Use of this method can suppress the occurrence of patients who do not respond to treatment, shorten the time until the amount of AdV reaches below the detection limit, shorten the treatment period, or provide a treatment with excellent safety.

[0013] (5) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof to a subject, the administering step being (i) administering BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof intravenously to the subject at 0.21 to 0.27 mg / kg twice weekly, or (ii) administering BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof intravenously to the subject at 9.9 to 14.3 mg / administration twice weekly. The subject is a patient not receiving cyclosporine, or the administering step comprises (i) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to the subject at 0.21-0.27 mg / kg twice a week, or (ii) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to the subject at 9.9-14.3 mg / administration twice a week, the subject being a patient receiving cyclosporine. By utilizing this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the amount of AdV reaches below the detection limit, shorten the treatment period, or provide a treatment with excellent safety.

[0014] (6) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering to a subject BCV, a pharma- ceutically acceptable salt or a solvate thereof, the administering step comprising (i) administering to the subject 0.38-0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly, or (ii) administering to the subject 18-22 mg / dose of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly, the duration of administration being terminated based on treatment discontinuation criteria, including the completion of the fourth week of treatment. This method allows for the termination of administration to be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration described above, and therefore particularly allows for a shortened treatment period.

[0015] (7) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering to a subject BCV, a pharma- ceutically acceptable salt or a solvate thereof, the administering step comprising (i) administering to the subject 0.38-0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly, or (ii) administering to the subject 18-22 mg / intravenously twice weekly, the duration of administration being terminated when both of the following conditions are met: (a) AdV is below the detection limit for two consecutive measurements of the amount of AdV in a subject's sample, and (b) the fourth week of treatment has elapsed. This method allows the end of administration to be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration described above, and therefore particularly allows for a shortened treatment period.

[0016] (8) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering to a subject BCV, a pharma- ceutically acceptable salt or a solvate thereof, the administering step comprising (i) administering to the subject 0.38-0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly, or (ii) administering to the subject 18-22 mg / intravenously twice weekly, the administration period being terminated when both of the following conditions are met: (a) AdV is negative for two consecutive measurements of the amount of AdV in a subject's sample, and (b) the fourth week of treatment has elapsed. This method allows the end of administration to be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration described above, and therefore particularly allows for a shortened treatment period.

[0017] (9) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering to a subject a pharmaceutical composition comprising BCV, a pharma- ceutically acceptable salt or a solvate thereof, the administering step comprising (i) administering to a subject an amount of the pharmaceutical composition equivalent to 0.38-0.42 mg / kg of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly, or (ii) administering to a subject an amount of the pharmaceutical composition equivalent to 18-22 mg / administration of BCV, a pharma- ceutically acceptable salt or a solvate thereof twice weekly intravenously. Use of this method can suppress the occurrence of patients who do not respond to treatment, shorten the time until the amount of AdV reaches below the detection limit, shorten the treatment period, or provide a treatment with excellent safety. From another aspect, according to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising a step of administering to a subject a pharmaceutical composition comprising BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof, the administering step comprising (i) administering to a subject an amount of the pharmaceutical composition equivalent to 0.38 to 0.42 mg / kg of BCV twice a week, or (ii) administering to a subject an amount of the pharmaceutical composition equivalent to 18 to 22 mg / administration twice a week. From another aspect, according to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising a step of administering to a subject a pharmaceutical composition comprising BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof, and a step of measuring the amount of AdV in a sample (e.g., blood or stool) from the subject. From another aspect, according to one embodiment of the present invention, there is provided a method for reducing the amount of AdV in a sample (e.g., blood or stool) from a subject, comprising a step of administering to a subject a pharmaceutical composition comprising BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof.

[0018] (10) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising administering BCV, a pharma- ceutically acceptable salt or solvate thereof to a human subject, the administering step being: (i) administering BCV, a pharma- ceutically acceptable salt or solvate thereof intravenously twice weekly at 0.4 mg / kg to a subject weighing less than 50 kg (provided that in the setting of coadministration with cyclosporine, the BCV dosage is reduced by 60%); or (ii) administering BCV, a pharma- ceutically acceptable salt or solvate thereof intravenously twice weekly to a subject weighing 50 kg or more. (c) administering a solvate of BCV intravenously at 20 mg / dose twice a week (provided that in the case of coadministration with cyclosporine, the BCV dose is reduced to 60%), the administration period being terminated based on the satisfaction of both of the following conditions: (a) AdV levels in a subject's sample are measured multiple times and AdV is below the limit of detection for two consecutive measurements, and (b) the fourth week of treatment has elapsed, the administration is administered by intravenous infusion over a period of two hours (e.g., continuous intravenous infusion), and the human subject is an allogeneic hematopoietic cell transplant patient. By utilizing this method, it is possible to suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV level reaches below the limit of detection, shorten the treatment period, or provide a treatment with excellent safety.

[0019] (11) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt or a solvate thereof to a subject, the administering step may comprise the steps of (i) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to the subject at 0.38 to 0.42 mg / kg once a week, or (ii) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to the subject at 18 to 22 mg / administration once a week. By utilizing this method, AdV infection or a disease associated with AdV infection can be treated.

[0020] (12) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt or a solvate thereof to a subject, the administering step may comprise the steps of (i) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to the subject at 0.58 to 0.62 mg / kg once a week, or (ii) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to the subject at 28 to 32 mg / administration once a week. By utilizing this method, AdV infection or a disease associated with AdV infection can be treated.

[0021] (13) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt or a solvate thereof to a subject, the administering step may comprise the steps of (i) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to a subject at 0.78 to 0.82 mg / kg once a week, or (ii) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to a subject at 38 to 42 mg / administration once a week. By utilizing this method, AdV infection or a disease associated with AdV infection can be treated.

[0022] (14) Method According to one embodiment of the present invention, there is provided a method for treating AdV infection or a disease associated with AdV infection, comprising the step of administering BCV, a pharma- ceutically acceptable salt or a solvate thereof to a subject, the administering step may comprise the steps of (i) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to a subject at 0.38 to 0.82 mg / kg once a week, or (ii) administering BCV, a pharma- ceutically acceptable salt or a solvate thereof intravenously to a subject at 18 to 42 mg / administration once a week. By utilizing this method, AdV infection or a disease associated with AdV infection can be treated.

[0023] (15) Method The methods of the embodiments of the present invention (e.g., (1) to (14) above) may include, for example, (i) a step of testing whether a subject is infected with AdV or has a disease associated with AdV infection, (ii) a step of identifying a subject having AdV infection or a disease associated with AdV infection, (iii) a step of identifying a subject in need of treatment for AdV infection or a disease associated with AdV infection, (iv) a step of identifying a subject in need of prevention of AdV infection or a disease associated with AdV infection, (v) a step of identifying a subject after allogeneic or autologous transplantation (e.g., hematopoietic cell transplantation), (vi) a step of identifying a subject in an immunosuppressed state, (vii) a step of identifying a subject after administration of an immunosuppressant, or (viii) a step of identifying a patient with an immunodeficiency syndrome. Furthermore, the methods of the embodiments of the present invention (e.g., (1) to (14) above) may or may not include the following, for example, when specified: a step of identifying a subject infected with cytomegalovirus (CMV), BK virus (BKV), Epstein-Barr virus (EBV), or Variola virus (VaV), a method aimed at preventing or treating a disease associated with CMV, BKV, EBV, or VaV infection.

[0024] (16) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt or a solvate thereof, and the treatment comprises (i) administering to a subject 0.38-0.42 mg / kg of BCV, a pharma- ceutical acceptable salt or a solvate thereof intravenously twice weekly, or (ii) administering to a subject 18-22 mg of BCV, a pharma- ceutical acceptable salt or a solvate thereof intravenously twice weekly. Use of this pharmaceutical composition can suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the detection limit, or shorten the treatment period.

[0025] (17) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt or a solvate thereof, the treatment comprising (i) administering BCV, a pharma- ceutical acceptable salt or a solvate thereof intravenously twice weekly at 0.38-0.42 mg / kg to a subject under a certain weight, or (ii) administering BCV, a pharma- ceutical acceptable salt or a solvate thereof intravenously twice weekly at 18-22 mg / dose to a subject under a certain weight, the specific weights of (i) and (ii) being the same and 48-52 kg. Use of this pharmaceutical composition can suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the detection limit, or shorten the treatment period.

[0026] (18) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt or a solvate thereof, the treatment comprising (i) administering BCV, a pharma- ceutical acceptable salt or a solvate thereof intravenously to a subject at 0.38-0.42 mg / kg twice weekly (provided that in a coadministration environment with cyclosporine, the BCV dose is reduced to 55-65%), or (ii) administering BCV, a pharma-ceutical acceptable salt or a solvate thereof intravenously to a subject at 18-22 mg / administration twice weekly (provided that in a coadministration environment with cyclosporine, the BCV dose is reduced to 55-65%). The use of this pharmaceutical composition can suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the detection limit, or shorten the treatment period.

[0027] (19) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt or solvate thereof, the treatment comprising (i) administering to a subject 0.38-0.42 mg / kg of BCV, a pharma- ceutical acceptable salt or solvate thereof intravenously twice weekly, or (ii) administering to a subject 18-22 mg / administration of BCV, a pharma- ceutical acceptable salt or solvate thereof intravenously twice weekly, the treatment being terminated when the administration period of BCV, a pharma- ceutical acceptable salt or solvate thereof is completed upon the satisfaction of both of the following conditions: (a) AdV levels in a subject's sample are measured multiple times, and AdV is below the detection limit for two consecutive measurements; and (b) the fourth week of treatment has elapsed. The use of this pharmaceutical composition allows the termination of administration to be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration method described above, thereby in particular shortening the treatment period.

[0028] (20) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt or a solvate thereof, and the treatment comprises (i) administering to a human subject an amount of the pharmaceutical composition equivalent to 0.38-0.42 mg / kg of BCV, a pharma- ceutical acceptable salt or a solvate thereof twice weekly intravenously, or (ii) administering to a human subject an amount of the pharmaceutical composition equivalent to 18-22 mg / administration of BCV, a pharma- ceutical acceptable salt or a solvate thereof twice weekly intravenously. Use of this pharmaceutical composition can suppress the occurrence of patients who do not respond to treatment, shorten the time until the AdV amount reaches below the detection limit, or shorten the treatment period. From another perspective, according to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt thereof, or a solvate thereof, wherein the treatment comprises (i) administering the pharmaceutical composition intravenously twice weekly to a human subject in an amount equivalent to 0.38 to 0.42 mg / kg of BCV, or (ii) administering the pharmaceutical composition intravenously twice weekly to a human subject in an amount equivalent to 18 to 22 mg / administration of BCV.

[0029] (21) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition for treating AdV infection or a disease associated with AdV infection, comprising BCV, a pharma- ceutical acceptable salt or solvate thereof, said treatment comprising (i) administering BCV, a pharma- ceutical acceptable salt or solvate thereof intravenously at 0.4 mg / kg twice weekly to a subject weighing less than 50 kg (provided that in the context of coadministration with cyclosporine, the BCV dosage is reduced by 60%), or (ii) administering BCV, a pharma- ceutical acceptable salt or solvate thereof intravenously at 20 mg twice weekly to a subject weighing 50 kg or more. and (b) administering the BCV or a pharmacopoeitic salt or a solvate thereof by continuous intravenous infusion over a period of 2 hours to the subject (provided that in the case of coadministration with cyclosporine, the BCV dosage is reduced to 60%), the treatment being terminated based on the fact that the administration period of the BCV, a pharmacopoeitic salt or a solvate thereof is terminated when the following two conditions are satisfied: (a) the amount of AdV in a subject's sample is measured multiple times and the amount of AdV is below the limit of detection for two consecutive measurements, and (b) the fourth week of treatment has elapsed, and the BCV, a pharmacopoeitic salt or a solvate thereof is administered by continuous intravenous infusion over a period of 2 hours. The use of this pharmaceutical composition can suppress the occurrence of patients who do not respond to treatment, shorten the time until the amount of AdV reaches below the limit of detection, or shorten the treatment period.

[0030] (22) Composition According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof, for use in the methods according to (1) to (15) above.

[0031] (23) Kit According to one embodiment of the present invention, there is provided a kit comprising the pharmaceutical composition according to any one of (16) to (22) above. The kit may also comprise, for example, an instruction manual, a buffer solution, a container, or a package.

[0032] (24) Use According to one embodiment of the present invention, there is provided a use of BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof for the manufacture of a pharmaceutical composition according to any one of (16) to (22) above.

[0033] In the embodiments of the present invention (e.g., (1) to (24) above), brincidofovir (BCV) includes a compound having a structure represented by the following formula: BCV can also be represented by the IUPAC name of [(2S)-1-(4-amino-2-oxopyrimidin-1-yl)-3-hydroxypropan-2-yl]oxymethyl-(3-hexadecoxypropoxy)phosphinic acid. BCV includes a compound represented by the CAS registry number of 444805-28-1. In the present specification, BCV is an abbreviation of brincidofovir, and they have the same meaning. [ka]

[0034] In the embodiment of the present invention (e.g., (1) to (24) above), adenovirus (AdV) is, for example, a type of DNA virus, and includes viruses that can cause AdV infection. In the present specification, AdV is an abbreviation of adenovirus, and they have the same meaning. AdV includes viruses of the Adenoviridae family. Viruses of the Adenoviridae family include viruses of the Mastadenovirus genus, for example. The therapeutic effect on AdV infection or diseases associated with AdV infection may be evaluated, for example, by observing the change over time in the amount of AdV in a subject sample after administration of a pharmaceutical composition. In this case, the therapeutic effect may be evaluated based on the fact that the amount of AdV shows a decreasing tendency. In addition, in this case, it may be determined that the therapeutic effect is present when the amount of AdV is significantly decreased compared to before administration of the pharmaceutical composition or when a negative control is administered. The amount of AdV may be measured, for example, by a method for measuring the amount of AdV DNA (e.g., quantitative PCR or immunochromatography). The measurement may be quantitative or qualitative.

[0035] In the embodiments of the present invention (e.g., (1) to (24) above), diseases associated with AdV infection include diseases caused by AdV infection. Diseases associated with AdV infection include, for example, adenoviremia, fever associated with AdV infection, symptomatic or asymptomatic AdV infection accompanied by the organ disorders described below, disseminated AdV infection accompanied by dysfunction of multiple organs or systemic symptoms, deterioration of the general condition due to AdV infection or death associated therewith, AdV myocarditis, AdV central nervous system infection, AdV kidney infection, digestive disease associated with AdV infection (e.g., hepatitis or gastroenteritis), respiratory infection associated with AdV infection (e.g., airway inflammation (e.g., rhinitis, pharyngitis, or tonsillitis) or pneumonia), eye disease associated with AdV infection (e.g., epidemic keratoconjunctivitis), pharyngoconjunctival fever associated with AdV infection, or AdV hemorrhagic cystitis.

[0036] In the embodiment of the present invention (e.g., (1) to (24) above), the amount of BCV, its pharma- ceutically acceptable salt, or a solvate thereof is 0.38 to 0.42 mg / kg, more preferably 0.39 to 0.41 mg / kg, and most preferably 0.4 mg / kg, from the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection. Effective treatment includes, for example, suppression of occurrence of patients who do not respond to treatment, shortening of the period until the amount of AdV reaches below the detection limit, shortening of the treatment period, or treatment with excellent safety. 0.38 to 0.42 mg / kg may be 0.38, 0.39, 0.4, 0.41, or 0.42 mg / kg, or may be within a range between any two of these values.

[0037] In the embodiments of the present invention (e.g., (1) to (24) above), 0.58 to 0.62 mg / kg as the amount of BCV, its pharma- ceutically acceptable salt, or a solvate thereof may be 0.59 to 0.61 mg / kg or 0.6 mg / kg. 0.58 to 0.62 mg / kg may be 0.58, 0.59, 0.6, 0.61, or 0.62 mg / kg, or may be within a range between any two of these values. 0.78 to 0.82 mg / kg may be 0.79 to 0.81 mg / kg or may be 0.8 mg / kg. 0.78 to 0.82 mg / kg may be 0.78, 0.79, 0.8, 0.81, or 0.82 mg / kg, or may be within a range between any two of these values. The range of 0.38 to 0.82 mg / kg may be 0.39 to 0.81 mg / kg, 0.4 to 0.8 mg / kg, or 0.4, 0.6, or 0.8 mg / kg. The range of 0.38 to 0.82 mg / kg may be 0.38, 0.4, 0.42, 0.5, 0.58, 0.6, 0.62, 0.7, 0.78, 0.8, or 0.82 mg / kg, or may be within a range between any two of these values.

[0038] In the embodiment of the present invention (e.g., (1) to (24) above), the amount of BCV, its pharma- ceutically acceptable salt, or solvate thereof is 18 to 22 mg / dose, more preferably 19 to 21 mg / dose, and most preferably 20 mg / dose, from the viewpoint of more effective treatment of AdV infection or diseases associated with AdV infection. Effective treatment includes, for example, suppression of occurrence of patients who do not respond to treatment, shortening of the period until the amount of AdV reaches below the detection limit, shortening of the treatment period, or treatment with excellent safety. 18 to 22 mg / dose may be 18, 19, 20, 21, or 22 mg / dose, or may be within the range of any two of these values. mg / dose may also be expressed in mg / body.

[0039] In the embodiment of the present invention (for example, the above (1) to (24)), the amount of 28 to 32 mg / injection of BCV, its pharma- ceutically acceptable salt, or a solvate thereof may be 29 to 31 mg / injection or 30 mg / injection. The amount of 28 to 32 mg / injection may be 28, 29, 30, 31, or 32 mg / injection, or may be within a range between any two of these values. The amount of 38 to 42 mg / injection may be 39 to 41 mg / injection or 40 mg / injection. The amount of 38 to 42 mg / injection may be 38, 39, 40, 41, or 42 mg / injection, or may be within a range between any two of these values. The amount of 18 to 42 mg / injection may be 19 to 41 mg / injection, 20 to 40 mg / injection, or may be 20, 30, or 40 mg / injection. The amount of 18 to 42 mg / dose may be 18, 20, 22, 25, 28, 30, 32, 35, 38, 40, or 42 mg / dose, or may be within a range between any two of these values.

[0040] In the embodiment of the present invention (e.g., (1) to (24) above), "as the amount of BCV, its pharma- ceutically acceptable salt, or solvate thereof" may mean, for example, the amount of BCV, its pharma- ceutically acceptable salt, or solvate thereof contained in a specific amount of pharmaceutical composition when the specific amount of pharmaceutical composition is administered to a subject. For example, when an amount A (mg / kg or mg / dose) of a pharmaceutical composition contains an amount B of BCV, its pharma- ceutically acceptable salt, or solvate thereof, and an amount C of an additive, the amount of BCV, its pharma- ceutically acceptable salt, or solvate thereof is the amount B. Here, an amount of a pharmaceutical composition equivalent to the amount B of BCV, its pharma- ceutically acceptable salt, or solvate thereof is the amount A of a pharmaceutical composition. In addition, "as the amount of BCV" may mean the amount of the BCV portion contained in a specific amount of pharmaceutical composition when the specific amount of pharmaceutical composition is administered to a subject. For example, when an amount D (mg / kg or mg / dose) of a pharmaceutical composition contains an amount E of BCV and an amount F of an additive, the amount of the BCV portion is the amount E. Here, the pharmaceutical composition in an amount equivalent to the amount E in terms of the amount of BCV is the pharmaceutical composition in an amount D. For example, when a pharmaceutical composition in an amount G (mg / kg or mg / dose) contains a pharma- ceutically acceptable salt of BCV in an amount H and an additive in an amount I, the amount of the BCV portion is the amount of the portion equivalent to the free form of BCV in the amount H (in other words, the amount obtained by subtracting the salt portion combined with the free form of BCV from the amount H). Here, the pharmaceutical composition in an amount equivalent to the portion equivalent to the free form of BCV in the amount H in terms of the amount of BCV is the pharmaceutical composition in an amount G. It is common in the pharmaceutical field to express the dosage based on the amount of the components, not the dosage of the final formulation. Therefore, those skilled in the art can understand the embodiment of the pharmaceutical composition or the treatment method in which the dosage is expressed based on the amount of the components.

[0041] In the embodiments of the present invention (e.g., (1) to (24) above), twice-weekly administration includes administration once on any one of days 1, 2, 3, 4, 5, 6, and 7, when a week is divided into days 1 to 7, and administration once on another day. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, twice-weekly administration is preferably on days 1 and 3, 4, or 5, and most preferably on days 1 and 4. Day 1 may be the start date of treatment, the first day of administration, or the first day of the week, and the day of the week may be Sunday, Monday, Tuesday, Wednesday, Thursday, Friday, or Saturday.

[0042] In the embodiments of the present invention (e.g., (1) to (24) above), the body weight of the subject to which BCV, its pharma- ceutically acceptable salt, or solvate thereof in (i) is administered intravenously at 0.38 to 0.42 mg / kg is less than a specific body weight, and the body weight of the subject to which BCV, its pharma-ceutically acceptable salt, or solvate thereof in (ii) is administered intravenously at 18 to 22 mg / dose is equal to or greater than a specific body weight, and the specific body weights of the subjects in (i) and (ii) may be the same, 48 to 52 kg. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, 48 to 52 kg is more preferably 49 to 51 kg, and most preferably 50 kg. 48 to 52 kg may be 48, 49, 50, 51, or 52 kg, or may be within a range between any two of these values. The specific body weight includes a predetermined body weight.

[0043] In the embodiments of the present invention (e.g., (1) to (24) above), the administration period of BCV, its pharma- ceutically acceptable salt, or a solvate thereof may be terminated based on a treatment discontinuation criterion. The use of the treatment discontinuation criterion allows the end of administration to be determined at an early stage, taking into account the patient response predicted from the particular dosage and administration described above, and therefore allows for a shortening of the treatment period in particular. The treatment discontinuation criterion may include, for example, the passage of four weeks of treatment from the first administration.

[0044] In the embodiments of the present invention (e.g., (1) to (24) above), the administration period of BCV, its pharma- ceutically acceptable salt, or solvate thereof may be terminated based on the fact that both of the following conditions are met: (a) the amount of AdV in a subject sample is measured multiple times, and AdV is below the detection limit for two consecutive measurements; and (b) the fourth week of treatment has elapsed. In this case, the end of administration can be determined at an early stage, taking into account the patient's response predicted from the specific dosage and administration method described above, and therefore the treatment period can be particularly shortened. The measurement of (a) above may be performed multiple times with an interval of 3 days or more. The measurement of (a) above may be performed on the same day as the administration day of BCV, its pharma- ceutically acceptable salt, or solvate thereof. The measurement of (a) above may be performed on the same day as the earlier administration day of twice weekly administration, or on the same day as the later administration day. The measurement of (a) above may be performed on one or two of the first, second, third, fourth, fifth, sixth, and seventh days of twice weekly administration. The measurement in (a) above may be performed at least once a week or twice a week for at least 4 weeks. The number of times may be, for example, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 30 or more times, or may be within the range of any two of these values. The above (a) may be performed when the amount of AdV in a subject sample is measured multiple times, and AdV is below the detection limit for two consecutive measurements in the latest two measurements. The latest two times may be, for example, the latest two times based on the time when it is determined whether to end the administration period (for example, the most recent measurement and the measurement one time before that). For example, if the administration period ends in 4 weeks, the latest two times may be the last measurement and the penultimate measurement in the 4 weeks. For example, if AdV does not reach below the detection limit within 4 weeks of administration, the latest two times may be the measurement at which AdV is first below the detection limit after the 5th week and the measurement next thereto. The most recent two times may be, for example, the last measurement within 4 weeks of administration and the first measurement in the fifth week of administration, if AdV first reached below the detection limit at the last measurement within 4 weeks of administration. The 3 or more days in (a) above is preferably 3 to 14 days."Three days or more" may be, for example, 3, 4, 5, 6, 7, 8, 10, 12, or 14 days, or may be any one or more of these values, or may be within a range of any two of these values. From another perspective, in the embodiments of the present invention (e.g., (1) to (24) above), the administration period of BCV, its pharma- ceutically acceptable salt, or a solvate thereof may be terminated based on the fact that both of the following conditions are met: (a) the amount of AdV in a subject's sample is measured multiple times, and AdV is negative for two consecutive times, and (b) the fourth week of treatment has elapsed. In this case, the end of administration can be determined at an early stage, taking into account the patient's response predicted from the above-mentioned specific dosage and administration method, and therefore the treatment period can be particularly shortened. From another perspective, in the embodiments of the present invention (e.g., (1) to (24) above), the administration period of BCV, its pharma-ceutically acceptable salt, or a solvate thereof may be terminated when the amount of AdV in a subject's sample is measured multiple times, and AdV is below the detection limit or negative for two consecutive times. In this case, the end of administration can be determined at an early stage, which in particular makes it possible to shorten the treatment period.

[0045] In the embodiments of the present invention (e.g., (1) to (24) above), AdV being below the detection limit includes, for example, AdV not reaching the detection limit when a PCR method (e.g., a quantitative PCR method (e.g., a real-time quantitative PCR method)) is performed. Being below the detection limit may also include a negative result. The PCR method described above has, for example, a detection limit of 25 copies / mL, a lower limit of quantification of 190 copies / mL, and an upper limit of quantification of 1×10 9 The detection limit of AdV may be, for example, 100, 75, 50, or 25 copies / mL. For the detection method of AdV, see, for example, Ison et al., Microbiol Spectr. 2016 Aug;4(4).

[0046] In the embodiments of the present invention (for example, (1) to (24) above), when treatment is performed under the environment of co-administration of cyclosporine and BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof, the dose of BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof may be reduced to 55 to 65%. The dose reduced to 55 to 65% is the same as the dose obtained by multiplying the original dose by 0.55 to 0.65. From the viewpoint of more effective treatment of AdV infection or a disease associated with AdV infection, 55 to 65% is more preferably 57 to 63%, further preferably 59 to 61%, and most preferably 60%. 55 to 65% may be 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65%, or may be within the range of any two of these values. In the above (i), when BCV, its pharma- ceutically acceptable salt, or a solvate thereof is intravenously administered at 0.38-0.42 mg / kg twice a week, the dose reduced by 55-65% includes 0.21-0.27 mg / kg. From the viewpoint of more effective treatment of AdV infection or diseases associated with AdV infection, 0.21-0.27 mg / kg is more preferably 0.23-0.25 mg / kg, and most preferably 0.24 mg / kg. 0.21-0.27 mg / kg may be 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, or 0.27 mg / kg, or may be within the range of any two of these values. In the above (ii), when BCV, its pharma- ceutically acceptable salt, or a solvate thereof is intravenously administered at 18 to 22 mg twice a week, the dose reduced by 55 to 65% includes 9.9 to 14.3 mg. From the viewpoint of more effective treatment of AdV infection or diseases associated with AdV infection, 9.9 to 14.3 mg is more preferably 11 to 13 mg, and most preferably 12 mg. 9.9 to 14.3 mg may be 9.9, 10, 11, 12, 13, 14, or 14.3 mg, or may be within the range of any two of these values.

[0047] In the embodiment of the present invention (e.g., (1) to (24) above), the dosage and administration of cyclosporine when cyclosporine and BCV, its pharma- ceutically acceptable salt, or a solvate thereof are administered in combination may be, for example, the dosage and administration of cyclosporine approved by PMDA or FDA at the time of filing the present application or known in the art. For example, for transplant patients, a dose of 6 to 16 mg / kg / day of cyclosporine may be orally administered twice a day from the first day after transplantation, and thereafter the dose may be reduced by 2 mg / kg per day or gradually decreased. The standard maintenance dose is a dose of 2 to 6 mg / kg / day, which may be increased or decreased as appropriate depending on symptoms. Cyclosporine may be administered by continuous intravenous infusion. Administration of cyclosporine does not affect the blood concentration of BCV. Cyclosporine includes a compound represented by the CAS Registry Number of 59865-13-3.

[0048] In embodiments of the present invention (e.g., (1) to (24) above), combination includes, when two or more treatments (e.g., administrations) are present, administering one treatment before, simultaneously with, or after the other treatment.

[0049] In the embodiments of the present invention (e.g., (1) to (24) above), the fourth week of treatment includes, for example, the case where four weeks have passed since the first administration, or the case where the second administration in the fourth week has been completed.

[0050] In the embodiments of the present invention (e.g., (1) to (24) above), the administration period includes, for example, the period from the first administration, after administration is repeated at a specific frequency (e.g., twice a week), until administration is discontinued. For example, when administration is performed twice a week for four weeks, the administration period may be four weeks. The administration period includes, for example, the period of continuous intravenous infusion and the interval period (e.g., the period during which continuous intravenous infusion is not received). The administration period includes the treatment period.

[0051] In the methods of the embodiments of the present invention (e.g., (1) to (15) above), the step of identifying a subject may include a step of identifying a subject as a subject for treatment, or a step of identifying a subject as a subject for administration of a pharmaceutical composition. The step of identifying a subject may include a step of selecting a subject, or a step of identifying a subject.

[0052] In embodiments of the present invention (e.g., (1) to (24) above), subjects having AdV infection or a disease associated with AdV infection may be identified based on detection of AdV DNA in a sample (e.g., blood) from the test subject, the amount of AdV DNA in the sample being significantly higher than that of a comparison subject (e.g., a healthy individual), or the amount of AdV in the sample being 1000 copies / ml or more or 10,000 copies / ml or more.

[0053] In the embodiments of the present invention (e.g., (1) to (24) above), the sample may include, for example, a biological sample. The sample may include, for example, a body fluid (e.g., blood (e.g., plasma, serum, or whole blood), a throat swab, saliva, urine, or cerebrospinal fluid), sputum, or stool. The sample may include, for example, a specimen. In treating a subject, the efficacy of treatment may be evaluated based on the amount of AdV in the subject's sample, and the amount of AdV may be used as an indicator for discontinuing treatment.

[0054] In an embodiment of the present invention (e.g., (1) to (24) above), the treatment includes exerting an effect that brings about a beneficial result in a patient with respect to a disease (e.g., AdV infection or a disease associated with AdV infection) or one or more symptoms associated with the disease (e.g., improvement, alleviation, mitigation, cure, remission or suppression (e.g., suppression of onset (e.g., prevention), suppression of progression, or suppression of recurrence) in a patient. The treatment may be performed by administering a therapeutically effective amount of BCV, a pharmaceutically acceptable salt thereof, or a solvate thereof to a subject. In an embodiment of the present invention (e.g., (1) to (24) above), the pharmaceutical composition may be produced, for example, by mixing an active ingredient with one or more pharmaceutically acceptable carriers and by any method known in the technical field of pharmaceutical science. Furthermore, the pharmaceutical composition may be in any form as long as it is used for treatment, and may be an active ingredient alone or a mixture of an active ingredient and any ingredient. Furthermore, the shape of the carrier is not particularly limited, and may be, for example, a solid or liquid (e.g., a buffer solution). The content of the carrier may be, for example, a pharmaceutically effective amount. The effective amount may be, for example, a pharmaceutically stable amount of the active ingredient. The amount of the active ingredient may be sufficient for stability or delivery. For example, the buffer is effective for stabilizing the active ingredient in the vial. The pharmaceutical composition may also contain a stabilizer (e.g., mannitol), a buffering agent (e.g., arginine), or a pH adjuster (e.g., NaOH). The dosage, administration interval, administration method, and administration route are not particularly limited and can be appropriately selected depending on the age and weight of the patient, symptoms, target organ, and the like. The pharmaceutical composition preferably contains a therapeutically effective amount, or an effective amount of the active ingredient that exerts a desired effect. In one embodiment of the present invention, the therapeutically effective amount includes an amount necessary for clinically observing improvement of symptoms in the patient. In one embodiment of the present invention, pharma- ceutical acceptable includes a state suitable for use in accordance with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. The components other than BCV in the pharmaceutical composition are not particularly limited as long as they do not impair the effects of the present invention, and can be appropriately selected according to the purpose. The therapeutic effect of AdV infection or a disease associated with AdV infection may be determined to be therapeutically effective when the amount of AdV in the patient is significantly reduced after administration of the pharmaceutical composition.

[0055] In the embodiments of the present invention (e.g., (1) to (24) above), the subject (including a patient) may be, for example, a subject diagnosed with AdV infection or a disease associated with AdV infection, a subject suspected of developing AdV infection or a disease associated with AdV infection, or a subject in need of treatment for AdV infection or a disease associated with AdV infection. The subject may be, for example, a subject in which AdV is detected in a sample, a subject in which the amount of AdV in a sample is increased compared to a comparison subject (e.g., a healthy individual), or a subject in which AdV in a sample is 1000 copies / ml or more or 10,000 copies / ml or more. The subject may be, for example, a subject who has experienced AdV infection or a disease associated with AdV infection. The subject may be, for example, an allogeneic transplant patient, an autologous transplant patient, or a hematopoietic stem cell transplant patient. The subject may be, for example, a patient with an immunodeficiency disease or condition, including a patient after allogeneic hematopoietic stem cell transplantation. A subject includes a human or a non-human mammal (e.g., one or more of a mouse, a guinea pig, a hamster, a rat, a mouse, a rabbit, a pig, a sheep, a goat, a cow, a horse, a cat, a dog, a marmoset, a monkey, or a chimpanzee, etc.). A subject includes a human adult patient or a human pediatric patient (e.g., a patient 2 months of age or older). A subject may be, for example, 0, 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 years old, or within a range of any two of these values. A subject includes a population of subjects.

[0056] In the embodiments of the present invention (e.g., (1) to (24) above), the subject of treatment with BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof is preferably an allogeneic hematopoietic cell transplant patient, from the viewpoint of providing a more effective treatment against AdV infection. Effective treatment includes, for example, suppression of the occurrence of treatment-refractory patients, shortening the time until the amount of AdV reaches below the detection limit, shortening the treatment period, or treatment with excellent safety.

[0057] In the embodiments of the present invention (e.g., (1) to (24) above), the route of administration of BCV, a pharma- ceutically acceptable salt thereof, or a solvate thereof (or a pharmaceutical composition containing them) to a subject (including a human subject) is preferably intravenous for effective treatment. The preferred form of administration is injection (e.g., intravenous injection) for effective treatment.

[0058] In the embodiments of the present invention (e.g., (1) to (24) above), the salt is not particularly limited and includes, for example, an inorganic salt or an organic salt (see, for example, Bharate et al., Drug Discov Today. 2021 Feb;26(2):384-398. or Berge et al., J Pharm Sci. 1977 Jan;66(1):1-19.). Salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Metal salts include, for example, alkali metal salts (sodium salts, potassium salts, etc.), alkaline earth metal salts (calcium salts, magnesium salts, barium salts, etc.), aluminum salts, and the like. Salts with organic bases include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, etc. Salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Salts with organic acids include, for example, salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, mesylic acid, tosylic acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc. Salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid, etc. Salts include pharma- ceutically acceptable salts. In one embodiment of the present invention, pharma- ceutically acceptable includes a form having reasonable benefits for pharmaceutical use. In one embodiment of the present invention, a form of the compound or a salt thereof includes a solvate form thereof. In an embodiment of the present invention (e.g., (1) to (24) above), a solvate includes a form of the compound formed by a solute and a solvent (e.g., see Healy et al., Adv Drug Deliv Rev. 2017 Aug 1;117:25-46).Solvates include, but are not limited to, for example, hydrates (e.g., monohydrates, dihydrates, trihydrates, etc.) or organic solvates (e.g., solvates with alcohols (e.g., methanol, ethanol, propanol, etc.), acetone, dimethylformamide, or ethyl acetate, etc.). Solvents include those that are capable of substantially maintaining the physiological activity of the solute after forming the solvate. Solvates include pharma- ceutically acceptable solvates.

[0059] In one embodiment of the present invention (e.g., (1) to (24) above), "significantly" may mean, for example, a state where a statistically significant difference is evaluated using a Student's t-test (one-tailed or two-tailed), where p<0.05 or p<0.01, or a state where a substantial difference is generated.

[0060] All publications cited herein are incorporated by reference in their entirety. In this specification, "or" is used when "at least one or more" of the items listed in the text can be employed. The same applies to "or." When it is specified in this specification that "within a range of two values," the range includes the two values ​​themselves. In this specification, "A to B" includes A and B and values ​​between A and B. In this specification, "having" includes being affected when it relates to a disease. In this specification, "the above (1) to (24)" includes reference to any one or more of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (12), (22), (23), or (24).

[0061] Although the embodiments of the present invention have been described above, these are merely examples of forms that may be included in the present invention, and the present invention is not limited to these, and various configurations other than those described above may be adopted. Furthermore, the present invention may be adopted in combination with each of the configurations or features described in the above embodiments, or independently. EXAMPLES

[0062] The present invention will be further explained below with reference to examples, but is not limited to these.

[0063] Example 1: Human clinical trials for the treatment of AdV infection A human clinical trial for the treatment of adenovirus (AdV) infection was conducted using the following procedure.

[0064] 1.1 Materials and Methods 1.1.1 Patient Patients aged 2 months or older who are immunosuppressed and have asymptomatic AdV infection or AdV disease, including hematopoietic stem cell transplant patients before immune reconstitution with transplanted cells has been achieved, organ transplant patients receiving immunosuppressants, and patients with immunodeficiency syndromes, and who have high levels of AdVemia (≥10,000 copies / ml in one sample, or ≥1000 copies / ml in two samples with an increased viral load in the second sample compared to the first).

[0065] 1.1.2 Drug Description Brincidofovir (BCV) injection is a sterile aqueous solution containing 10 mg / mL BCV. Drug Overview Product name: Brincidofovir (BCV) Dosage form: Injection Unit dose: 10mg / mL (1mL per vial) Route of administration: Intravenous injection Physical description: Clear, colorless solution in a sterile glass bottle Storage method: Refrigerate (2~8℃) Administration method: Twice a week (days 1 and 4) administer by continuous intravenous infusion over 2 hours.

[0066] 1.1.3 Dosage Cohort 1: 0.2 mg / kg (10 mg / dose if body weight is 50 kg or more) administered twice weekly Cohort 2: 0.3 mg / kg (15 mg / dose if body weight is 50 kg or more) administered twice weekly Cohort 3: 0.4 mg / kg (20 mg / dose if body weight is 50 kg or more) administered twice weekly

[0067] 1.1.4 Drug Administration The dosage of BCV 10mg / mL injection is prepared based on the patient's weight. The following kit is used to prepare and administer the intravenous injection: Intravenous Bag: Glucose 5%, 100mL, Non-PVC, DEHP Free Intravenous Tubing: Tubing contains no plasticizers and is DEHP-free. Intravenous pumps: Use approved tubing. Preparation: Using a sterile syringe and needle, transfer 1 mL of BCV intravenous solution from one vial into a 100 mL glucose 5% intravenous bag to make the diluted solution. If the dose exceeds 10 mg, prepare an additional dose of diluted solution using the same procedure as above. Gently invert the bag at least five times to mix. Do not vigorously shake the solution in the vial or the diluted solution in the bag.

[0068] Administer the appropriate amount of diluent based on the patient's weight. Administer each dose intravenously at a steady rate over 2 hours. After administration is complete, flush the IV line with glucose 5% or dextrose 5% to ensure all active medication is removed from the IV line. If required per facility practice, the glucose 5% or dextrose 5% flush may be followed by a normal saline flush. Diluents should generally be prepared at the time of use, not the day before.

[0069] Subjects 101-12 in cohort 2 and subjects 101-15, 101-18, and 110-06 in cohort 3 will receive the immunosuppressant cyclosporine during treatment with intravenous BCV. A preliminary PK study in healthy subjects showed that coadministration of BCV and cyclosporine significantly increased plasma BCV exposure. When BCV and cyclosporine were administered simultaneously, the AUC inf and C max The AUC of plasma BCV increased by approximately 3.4-fold and 2.3-fold, respectively, when BCV was administered alone. When cyclosporine was administered over 2 hours after the end of intravenous BCV administration, the AUC infand C max The AUC of plasma BCV after BCV administration alone was increased by approximately 1.8 and 1.3 times, respectively. inf and C max were roughly equivalent. In consideration of the above, for the above patients taking cyclosporine, all doses shown in 1.1.3 (Cohorts 1 to 3) above will be reduced to 60%. When cyclosporine is administered as an oral agent or injection BID (twice a day), it will be administered with an interval of 2 hours from the end of the BCV intravenous injection. When cyclosporine is administered as a 24-hour continuous infusion, there is no interval.

[0070] 1.1.5 Test period The study duration will be at least 9 weeks, based on a 1-week screening period, a treatment period of at least 4 weeks, and a post-treatment follow-up period of 30 days. At screening, after the patient has given informed consent, a screening assessment will be performed to determine eligibility for the study. On the first day of the first week of the treatment period, patients will be assigned a dose based on the applicable cohort (see 1.1.3 above, Cohorts 1-3). The treatment period will be a minimum of 4 weeks and a maximum of 14 weeks, with termination based on the treatment discontinuation criteria described below. For patients who, in the physician's opinion, are assessed as being at high risk for AdV infection / disease recurrence, the treatment period may be extended for up to 10 weeks, even if the patient has completed the 4-week treatment period, if the AdV load is not confirmed on two consecutive measurements at least 3 days apart. All patients will be followed up for 30 days after the last dose. Adverse events will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 (grades 1-5). Based on the results of the review of the safety data for cohort 1, a decision will be made whether to start cohort 2. Similarly, the decision to start Cohort 3 will be based on the review of safety data from Cohort 2. If grade ≥ 3 adverse events are observed in > 25% of all subjects in the previous cohort, enrollment in the new cohort will be immediately halted.

[0071] The timing of the end of the treatment period based on the treatment stopping criteria is explained below. The treatment stopping criteria are that the adenovirus in the subject's sample is measured multiple times, and the adenovirus is below the limit of detection in the two most recent consecutive measurements, and that the fourth week of treatment has passed. To confirm that AdV viremia is below the limit of detection (LOD), two consecutive results with plasma viral load below the LOD are required. After the initial result is reported as below the LOD, a confirmatory blood draw must be performed at least 3 days (2 full days) and no later than 14 days (13 full days) after the initial sample was collected. Patients receiving intravenous BCV treatment will continue treatment for 4 weeks even if AdV viremia is confirmed to be below the LOD, unless excluded by guidelines for managing BCV-specific adverse events. If plasma AdV load is confirmed to be below the LOD on two consecutive occasions before the completion of 4 weeks of BCV treatment, the patient will continue the specified BCV treatment for up to 4 weeks. If AdV viremia is present by day 1 of week 5 and confirmed by serial weekly viral load testing, BCV treatment may be continued for up to 14 weeks. Patients who have received BCV for 4 weeks may discontinue intravenous BCV treatment and proceed to post-treatment follow-up once AdV viremia is confirmed below the LOD by two consecutive measurements of plasma viral load.

[0072] 1.1.6 Blood samples for viremia analysis Blood from each patient was collected in a K2EDTA tube, mixed by inversion 8 to 10 times, and then centrifuged at 1100 to 1300 × g for 10 minutes. Plasma was separated immediately after collection or within 30 minutes after collection. Plasma was frozen and stored at -70°C and analyzed for AdV-related blood glucose levels by real-time qPCR (detection limit 25 copies / mL, lower limit of quantification 190 copies / mL, upper limit of quantification 1 × 10 9 copies / mL).

[0073] 1.2 Clinical trial data Figures 1 to 3 show the test results for cohorts 1 to 3. In the horizontal axis of Figures 1 to 3, W in W1D1 means week and D means day (i.e., W1D1 is the first day of the first week). The same applies to W2D1 and onwards. The vertical axis of Figures 1 to 3 shows the amount of adenovirus in plasma. Below the LLOQ line is below the detection limit. Cohorts 1 to 3 include male or female patients aged 0 to 80 years and weighing 5.4 to 82.4 kg. Cohort 1 included one patient weighing 50 kg or more, and cohorts 2 and 3 included two each.

[0074] In cohort 1, two patients achieved undetectable AdV viral loads; one of the two patients relapsed, and one patient died. In cohort 2, five patients achieved undetectable AdV viral loads; the five patients had longer time to achieve undetectable viral loads overall, and one patient died.

[0075] In cohort 3, the AdV amount reached below the detection limit in all cases (10 cases). In addition, none of the patients relapsed or died. Furthermore, the time to reach below the detection limit was short overall in the 10 cases. In cohort 3, 8 patients reached below the detection limit within 4 weeks, and the remaining 2 patients reached below the detection limit in the 5th and 6th weeks. From the above, it was shown that in cohort 3, the occurrence of patients who did not respond to treatment can be suppressed. In addition, it was shown that the treatment period can be shortened in cohort 3 because the time to reach below the detection limit is short. Furthermore, in cohort 3, it was shown that the treatment period can be particularly shortened because the administration period can be terminated based on the above treatment discontinuation criteria.

[0076] Adverse events related to BCV were as follows: Cohort 1: 110-01, diarrhea - grade 2 (possible), 109-01, elevated AST - grade 1 (probable), elevated AST - grade 1 (probable), elevated LDH - grade 1 (possible); Cohort 2: 101-09, diarrhea - grade 3 (possible), 109-03, nausea - grade 1 (possible), 101-14, hypertransaminasemia - grade 3 (possible); Cohort 3: 102-02, increased alanine aminotransferase - grade 3 (possible), increased aspartate aminotransferase - grade 3 (possible), 109-04, palpitations - grade 1 (possible), nausea - grade 1 (possible). There were zero grade 3 adverse events in cohort 1, two in cohort 2, and one in cohort 3. Cohort 3 received a higher dose than cohort 2, but had a lower incidence of grade 3 adverse events.

[0077] 1.3. Discussion BCV injection is effective in treating AdV infection and preventing AdV infection in immunocompromised patients. Intravenous administration of 0.4 mg / kg (20 mg if the patient weighs 50 kg or more) twice a week showed a significantly excellent therapeutic effect. This administration method can suppress the occurrence of patients who do not respond to treatment. This administration method can shorten the treatment period because it is short in the period until the AdV amount reaches below the detection limit and recurrence is suppressed. This administration method can particularly shorten the treatment period by applying the above-mentioned treatment discontinuation criteria. In addition, shortening the treatment period brings benefits such as suppressing the emergence of resistant strains, reducing the physical burden on patients, reducing the incidence of adverse events, and reducing treatment costs. This administration method is excellent in safety because the incidence of adverse events is low.

[0078] Example 2: Analysis of stool AdV load In the clinical trial of Example 1, the amount of AdV in the stool of a patient was examined. As shown in Figure 4, the stool of the patient was collected and tested. In the figure, D means detected, ND means not detected, and NP means not performed. Real-time qPCR was used to analyze the amount of AdV.

[0079] In cohort 1, 1 of 8 patients had undetectable AdV loads during the study period. In cohort 2, 3 of 9 patients had undetectable AdV loads during the study period. 1 of 3 patients had detectable AdV loads the following week.

[0080] In cohort 3, 5 out of 8 patients had undetectable AdV levels during the study period. Although there were no drugs that could eliminate AdV in stool, the administration method used in cohort 3 demonstrated that AdV in stool could be effectively eliminated.

[0081] Example 3: Lymphocyte analysis In the clinical trial of Example 1, the number of lymphocytes in the plasma of patient 110-05 of cohort 3 was examined. Figure 5 shows the measurement results of lymphocyte count, AdV amount, and ALT value. The AdV amount was below the detection limit at week 3, while lymphocytes showed a tendency to increase. The tendency of lymphocytes to increase suggests that the immune system related to lymphocytes was restored, and thus AdVemia is unlikely to recur.

[0082] Example 4: Human clinical trials for the treatment of AdV infection The following steps will be used to conduct a human clinical trial for the treatment of adenovirus (AdV) infection.

[0083] 4.1 Materials and Methods 4.1.1 Patient Immunosuppressed patients aged 2 months or older with asymptomatic AdV infection or disease, including hematopoietic stem cell transplant patients before immune reconstitution with transplanted cells has been achieved, organ transplant patients receiving immunosuppressants, and patients with immunodeficiency syndromes.

[0084] 4.1.2 Drug Description Brincidofovir (BCV) injection is a sterile aqueous solution containing 10 mg / mL BCV. Drug Overview Product name: Brincidofovir (BCV) Dosage form: Injection Unit dose: 10mg / mL (1mL per vial) Route of administration: Intravenous injection Physical description: Clear, colorless solution in a sterile glass bottle Storage method: Refrigerate (2~8℃) Administration: Continuous intravenous infusion over 2 hours once weekly.

[0085] 4.1.3 Dosage Cohort 4: 0.4 mg / kg (20 mg / dose if body weight is 50 kg or more) administered once weekly Cohort 5: 0.6 mg / kg (30 mg / dose if body weight is 50 kg or more) administered once weekly Cohort 6: 0.8 mg / kg (40 mg / dose if body weight is 50 kg or more) administered once weekly

[0086] 4.1.4 Drug Administration The dosage of BCV 10mg / mL injection is prepared based on the patient's weight. The following kit is used to prepare and administer the intravenous injection: Intravenous Bag: Glucose 5%, 100mL, Non-PVC, DEHP Free Intravenous Tubing: Tubing contains no plasticizers and is DEHP-free. Intravenous pumps: Use approved tubing. Preparation: Using a sterile syringe and needle, transfer 1 mL of BCV intravenous solution from one vial into a 100 mL glucose 5% intravenous bag to make the diluted solution. If the dose exceeds 10 mg, prepare an additional dose of diluted solution using the same procedure as above. Gently invert the bag at least five times to mix. Do not vigorously shake the solution in the vial or the diluted solution in the bag.

[0087] Administer the appropriate amount of diluent based on the patient's weight. Administer each dose intravenously at a steady rate over 2 hours. After administration is complete, flush the IV line with glucose 5% or dextrose 5% to ensure all active medication is removed from the IV line. If required per facility practice, the glucose 5% or dextrose 5% flush may be followed by a normal saline flush. Diluents should generally be prepared at the time of use, not the day before.

[0088] Previous PK studies in healthy subjects have shown that coadministration of BCV and cyclosporine significantly increases plasma BCV exposure. inf and C max The AUC of plasma BCV increased by approximately 3.4-fold and 2.3-fold, respectively, when BCV was administered alone. When cyclosporine was administered over 2 hours after the end of intravenous BCV administration, the AUC inf and C max The AUC of plasma BCV after BCV administration alone was increased by approximately 1.8 and 1.3 times, respectively. inf and C max were roughly equivalent. In consideration of the above, for the above patients taking cyclosporine, all doses shown in 4.1.3 (Cohorts 4 to 6) above will be reduced to 60%. When cyclosporine is administered as an oral agent or injection BID (twice a day), it will be administered with an interval of 2 hours from the end of the BCV intravenous injection. When cyclosporine is administered as a 24-hour continuous infusion, there is no interval.

[0089] 4.1.5 Test period The study duration will be at least 9 weeks, based on a 1-week screening period, a treatment period of at least 4 weeks, and a post-treatment follow-up period of 30 days. At screening, after the patient has given informed consent, a screening assessment will be performed to determine eligibility for the study. On the first day of the first week of the treatment period, patients will be assigned a dose based on the applicable cohort (see 4.1.3 above, cohorts 4-6). The treatment period will be a minimum of 4 weeks and a maximum of 14 weeks, with termination based on the treatment discontinuation criteria described below. For patients who, in the physician's opinion, are assessed to be at high risk for AdV infection / disease recurrence, the treatment period may be extended for up to 10 weeks, even if the patient has completed the 4-week treatment period, if the AdV load is not confirmed on two consecutive measurements at least 3 days apart. All patients will be followed up for 30 days after the last dose. Adverse events will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 (grades 1-5). In cohort 4, patients will be enrolled with the initially planned dosing regimen of 0.4 mg / kg or 20 mg IV once weekly. If tolerability is confirmed in cohort 4 (n=3 patients), cohort 5 will be initiated and BCV will be increased to 0.6 mg / kg or 30 mg IV once weekly. If ≤1 DLT (dose-limiting toxicity) is observed in cohort 5 (n=3 patients), cohort 6 will be initiated and BCV will be increased to 0.8 mg / kg or 40 mg IV once weekly (n=6).

[0090] The end of the treatment period based on the treatment discontinuation criteria is explained below. Treatment discontinuation criteria are when the adenovirus in the subject's sample is measured multiple times and the adenovirus is below the limit of detection in the two most recent consecutive measurements, and 4 weeks have passed since the first dose. To confirm that AdV viremia is below the limit of detection (LOD), two consecutive results with plasma viral load below the LOD are required. After the initial result is reported as below the LOD, a confirmatory blood draw must be performed at least 3 days (2 full days) and no later than 14 days (13 full days) after the initial sample was collected. Patients receiving intravenous BCV treatment will continue treatment for 4 weeks even if AdV viremia is confirmed to be below the LOD, unless excluded by guidelines for managing BCV-specific adverse events. If plasma AdV load is confirmed to be below the LOD on two consecutive occasions before the completion of 4 weeks of BCV treatment, patients will continue the specified BCV treatment for up to 4 weeks. If AdV viremia is present by day 1 of week 5 and confirmed by serial weekly viral load testing, BCV treatment may be continued for up to 14 weeks. Patients who have received BCV for 4 weeks may discontinue intravenous BCV treatment once AdV viremia is confirmed below the LOD by two consecutive measurements of plasma viral load after follow-up after treatment.

[0091] 4.1.6 Blood samples for viremia analysis Blood from each patient was collected in a K2EDTA tube, mixed by inversion 8-10 times, and then centrifuged at 1100-1300 x g for 10 minutes to separate plasma immediately or within 30 minutes of collection. Plasma was frozen and stored at -70°C and analyzed for AdV-related blood glucose levels using real-time qPCR.

[0092] 4.2 Clinical trial data Patients in cohorts 4 to 6 achieved undetectable AdV loads during the study period. The incidence of adverse events was particularly suppressed in cohort 4.

[0093] The present invention has been described above based on the embodiments. However, these embodiments are merely illustrative, and it will be understood by those skilled in the art that various modifications are possible and that such modifications are also within the scope of the present invention.

Claims

1. A pharmaceutical composition for treating an adenovirus infection or a disease associated with an adenovirus infection, comprising: Contains brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof, The treatment comprises: (i) administering 0.38-0.42 mg / kg of brincidofovir, a pharma- ceutically acceptable salt or solvate thereof intravenously to a human subject twice weekly; or (ii) administering 18-22 mg / dose of brincidofovir, a pharma- ceutically acceptable salt or solvate thereof intravenously to a human subject twice weekly; Pharmaceutical compositions.

2. The pharmaceutical composition according to claim 1, wherein said 0.38 to 0.42 mg / kg is 0.4 mg / kg, and said 18 to 22 mg / dose is 20 mg / dose.

3. The pharmaceutical composition according to claim 1 or 2, wherein the subject in (i) has a body weight less than a specific body weight, the subject in (ii) has a body weight equal to or greater than a specific body weight, and the specific body weights of (i) and (ii) are the same and are between 48 kg and 52 kg.

4. The pharmaceutical composition of claim 2, wherein the subject in (i) has a body weight less than a specific body weight, the subject in (ii) has a body weight equal to or greater than a specific body weight, and the specific body weights of (i) and (ii) are the same, 50 kg.

5. The pharmaceutical composition according to any one of claims 1 to 4, comprising brincidofovir.

6. The pharmaceutical composition according to any one of claims 1 to 5, which is for treating an adenovirus infection or an adenovirus infectious disease.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the administration period of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof is terminated based on a treatment discontinuation criterion.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the treatment discontinuation criteria comprises having completed the fourth week of treatment.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the administration period of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof is terminated based on the fact that both of the following conditions are satisfied: (a) the amount of adenovirus in a blood sample from the subject is measured multiple times, and the amount of adenovirus is below the limit of detection in two consecutive measurements; and (b) the fourth week of treatment has elapsed.

10. 5. The pharmaceutical composition of claim 4, wherein the administration period of brincidofovir, a pharma- ceutical acceptable salt, or a solvate thereof is terminated based on the fact that both of the following conditions are met: (a) the amount of adenovirus in a subject's sample is measured multiple times and the amount of adenovirus is below the limit of detection in two consecutive measurements; and (b) the fourth week of treatment has elapsed.

11. The pharmaceutical composition according to claim 9 or 10, wherein the measurement (a) is carried out multiple times at intervals of 3 to 14 days.

12. The pharmaceutical composition according to claim 11, wherein (a) is a case in which the amount of adenovirus in a subject sample is measured multiple times and the amount of adenovirus is below the detection limit in two consecutive measurements in the most recent two measurements.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the dosage of brincidofovir, its pharma- ceutically acceptable salt, or its solvate in (i) and (ii) is reduced by 55-65% when the treatment is carried out in the context of concomitant administration of cyclosporine and brincidofovir, its pharma- ceutically acceptable salt, or its solvate.

14. The pharmaceutical composition of claim 13, wherein the 55-65% is 60%.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the treatment is administered by intravenous infusion of brincidofovir, a pharma- ceutically acceptable salt thereof, or a solvate thereof over a period of 1.5 to 4 hours.

16. The pharmaceutical composition of claim 15, wherein said 1.5 to 4 hours is 2 hours.

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